U.S. patent application number 13/501130 was filed with the patent office on 2012-08-02 for aryl aminopyridine pde10 inhibitors.
Invention is credited to Michael J. Breslin, Christopher D. Cox, Izzat T. Raheem.
Application Number | 20120196856 13/501130 |
Document ID | / |
Family ID | 43922484 |
Filed Date | 2012-08-02 |
United States Patent
Application |
20120196856 |
Kind Code |
A1 |
Breslin; Michael J. ; et
al. |
August 2, 2012 |
ARYL AMINOPYRIDINE PDE10 INHIBITORS
Abstract
The present invention is directed to aryl aminopyridine
compounds which are useful as therapeutic agents for the treatment
of central nervous system disorders associated with
phosphodiesterase 10 (PDE10). The present invention also relates to
the use of such compounds for treating neurological and psychiatric
disorders, such as schizophrenia, psychosis or Huntington's
disease, and those associated with striatal hypofunction or basal
ganglia dysfunction.
Inventors: |
Breslin; Michael J.; (Drexel
Hill, PA) ; Cox; Christopher D.; (Harleysville,
PA) ; Raheem; Izzat T.; (North Wales, PA) |
Family ID: |
43922484 |
Appl. No.: |
13/501130 |
Filed: |
October 26, 2010 |
PCT Filed: |
October 26, 2010 |
PCT NO: |
PCT/US10/54009 |
371 Date: |
April 10, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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61256466 |
Oct 30, 2009 |
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Current U.S.
Class: |
514/234.5 ;
514/235.2; 514/235.5; 514/255.05; 514/293; 514/300; 514/307;
514/314; 514/332; 544/124; 544/127; 544/128; 544/405; 546/113;
546/122; 546/144; 546/176; 546/264; 546/82 |
Current CPC
Class: |
C07D 471/04 20130101;
C07D 413/14 20130101; C07D 213/69 20130101; A61P 25/00 20180101;
C07D 471/14 20130101; A61P 25/22 20180101; C07D 401/14 20130101;
A61P 25/18 20180101 |
Class at
Publication: |
514/234.5 ;
544/124; 514/235.5; 544/405; 514/255.05; 546/122; 514/300; 546/264;
514/332; 544/127; 546/144; 514/307; 546/82; 514/293; 546/176;
514/314; 544/128; 514/235.2; 546/113 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 401/14 20060101 C07D401/14; A61K 31/497 20060101
A61K031/497; C07D 471/04 20060101 C07D471/04; A61K 31/4375 20060101
A61K031/4375; A61P 25/22 20060101 A61P025/22; A61K 31/4725 20060101
A61K031/4725; C07D 471/14 20060101 C07D471/14; A61K 31/4709
20060101 A61K031/4709; A61K 31/437 20060101 A61K031/437; A61P 25/00
20060101 A61P025/00; A61P 25/18 20060101 A61P025/18; C07D 413/14
20060101 C07D413/14; A61K 31/444 20060101 A61K031/444 |
Claims
1. A compound of the formula I: ##STR00037## wherein: X is --CH--
or N, Y is --CH-- or N, and Z is --CH-- or N, with the proviso that
at least one of X, Y and Z is N; R.sup.1 is selected from the group
consisting of: (1) hydrogen, (2) halogen, (4) C.sub.1-6alkyl, which
is unsubstituted or substituted with halogen, hydroxyl, or phenyl,
and (5) --O--C.sub.1-6alkyl, which is unsubstituted or substituted
with halogen, hydroxyl or phenyl; R.sup.2a, R.sup.2b and R.sup.2c
are independently selected from the group consisting of: (1)
hydrogen, (2) halogen, (3) hydroxyl, (4) C.sub.1-6alkyl, which is
unsubstituted or substituted with halogen, hydroxyl, phenyl or
napthyl, (5) --O--C.sub.1-6alkyl, which is unsubstituted or
substituted with halogen, hydroxyl or phenyl, (6) phenyl, which is
unsubstituted or substituted with halogen, hydroxyl,
--O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is unsubstituted or
substituted with fluoro, (7) heteroaryl, which is unsubstituted or
substituted with halogen, hydroxyl, --O--C.sub.1-6alkyl or
C.sub.1-6alkyl, which is unsubstituted or substituted with fluoro,
(8) --O--phenyl, which is unsubstituted or substituted with
halogen, hydroxyl, --O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is
unsubstituted or substituted with fluoro, (9) --NH-C.sub.1-6alkyl,
or --N(C.sub.1-6alkyl)(C.sub.1-6alkyl), which is unsubstituted or
substituted with halogen, hydroxyl, --O--C.sub.1-6alkyl or
C.sub.1-6alkyl, which is unsubstituted or substituted with fluoro,
(10) --CO.sub.2H, (11) --CN, and (12) --NO.sub.2, or R.sup.2a and
R.sup.2b may be joined together to form a phenyl, pyridyl or
piperidinyl ring, which is unsubstituted or substituted with
R.sup.2c; R.sup.3 and R.sup.4 are independently selected from the
group consisting of: (1) hydrogen, and (2) C.sub.1-6alkyl, which is
unsubstituted or substituted with R.sup.14, or R.sup.3 and R.sup.4
may be joined together to form a heterocyclyl, which is
unsubstituted or substituted with halogen, hydroxyl, phenyl,
pyridyl, --O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is
unsubstituted or substituted with halogen, hydroxyl or phenyl;
R.sup.14 is selected from the group consisting of: (1) hydroxyl,
(2) halogen, (3) C.sub.1-6alkyl, (4) --C.sub.3-6cycloalkyl, (5)
--O--C.sub.1-6 alkyl, (6) --O(C.dbd.O)--C.sub.1-6alkyl, (7) .dbd.O,
(8) --CO.sub.2H, (9) --CO.sub.2--C.sub.1-6alkyl, (10)
--NH(C.dbd.O)--C.sub.1-6alkyl,
--N(C.sub.1-6alkyl)(C.dbd.O)--C.sub.1-6alkyl,
--NH(C.dbd.O)--O--C.sub.1-6alkyl,
--N(C.sub.1-6alkyl)(C.dbd.O)--O--C.sub.1-6alkyl, which is
unsubstituted or substituted with halogen, hydroxyl,
--O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is unsubstituted or
substituted with fluoro, (11) --NH--C.sub.1-6alkyl, or
--N(C.sub.1-6alkyl)-C.sub.1-6alkyl, which is unsubstituted or
substituted with halogen, hydroxyl, --O--C.sub.1-6alkyl or
C.sub.1-6alkyl, which is unsubstituted or substituted with fluoro,
(12) phenyl, which is unsubstituted or substituted with halogen,
hydroxyl, --O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is
unsubstituted or substituted with fluoro, (13) heteroaryl, which is
unsubstituted or substituted with halogen, hydroxyl,
--O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is unsubstituted or
substituted with fluoro, (14) heterocyclyl, which is unsubstituted
or substituted with halogen, hydroxyl, --O--C.sub.1-6alkyl or
C.sub.1-6alkyl, which is unsubstituted or substituted with fluoro,
and (15) --CN; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein: X is N, Y is --CH--, and Z is
--CH--; X is X is --CH--, Y is --N, and Z is --CH--; X is --CH--, Y
is --CH--, and Z is N; or X is N, Y is --CH--, and Z is N.
3. The compound of claim 1 wherein R.sup.1 is selected from the
group consisting of: (1) hydrogen, and (2) halogen.
4. The compound of claim 1 wherein R.sub.2a, R.sub.2b and R.sup.2c
are independently selected from the group consisting of: (1)
hydrogen, (2) halogen, (3) hydroxyl, (4) C.sub.1-6alkyl, which is
unsubstituted or substituted with halogen, hydroxyl, phenyl or
napthyl, (5) --O--C.sub.1-6alkyl, which is unsubstituted or
substituted with halogen, hydroxyl or phenyl, (6) phenyl, which is
unsubstituted or substituted with halogen, hydroxyl,
--O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is unsubstituted or
substituted with fluoro, (7) heteroaryl, which is unsubstituted or
substituted with halogen, hydroxyl, --O--C.sub.1-6alkyl or
C.sub.1-6alkyl, which is unsubstituted or substituted with fluoro,
(8) --O--phenyl, which is unsubstituted or substituted with
halogen, hydroxyl, --O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is
unsubstituted or substituted with fluoro, (9) --NH-C.sub.1-6alkyl,
or --N(C.sub.1-6alkyl)(C.sub.1-6alkyl), which is unsubstituted or
substituted with halogen, hydroxyl, --O--C.sub.1-6alkyl or
C.sub.1-6alkyl, which is unsubstituted or substituted with fluoro,
(10) --CO.sub.2H, (11) --CN, and (12) --NO.sub.2, or R.sup.2a and
R.sup.2b may be joined together to form a phenyl, pyridyl or
piperidinyl ring, which is unsubstituted or substituted with
R.sup.2c.
5. The compound of claim 4 wherein R.sup.2a, R.sup.2b and R.sup.2c
are independently selected from the group consisting of: (1)
hydrogen, (2) methyl, (3) ethyl, (4) trifluromethyl, and (5)
methoxy.
6. The compound of claim 4 wherein R.sup.2a and R.sup.2b are joined
together to form a phenyl, pyridyl or piperidinyl ring.
7. The compound of claim 1 wherein R.sup.3 and R.sup.4 are joined
together to form a pyrrolopyridinyl, tetrahydronapthyridinyl,
tetrahydropryido-napthyridinyl, or morpholinyl ring, which is
unsubstituted or substituted with a substituent selected from the
group consisting of: (1) halogen, (2) hydroxyl, (3) pyridyl, (4)
C.sub.1-6alkyl, which is unsubstituted or substituted with halogen,
hydroxyl or phenyl, and (5) --O--C.sub.1-6alkyl, which is
unsubstituted or substituted with halogen, hydroxyl or phenyl.
8. The compound of claim 7 wherein R.sup.3 and R.sup.4 are joined
together to form a tetrahydronapthyridinyl ring.
9. The compound of claim 7 wherein R.sup.3 and R.sup.4 are joined
together to form a morpholinyl ring.
10. A compound which is selected from the group consisting of:
4-(2-{4-[(3,4-dimethoxypyridin-2-yl)methoxy]phenyl}pyridin-3-yl)morpholin-
e; 2-{4-[(3,5-dimethoxy-4-methylpyridin-2-yl)methoxy]phenyl}-3-[3
-(3 -methylphenyl)-piperidin-1-yl]pyrazine;
6-(3-{4-[(4-methoxy-3,5-dimethylpyridin-2-yl)-methoxy]-phenyl}pyridin-2-y-
l)-5,6,7,8-tetrahydro-1,6-naphthyridine; 2-
{4-[(4-methoxy-3,5-dimethylpyridin-2-yl)methoxy]phenyl}-N-methyl-N-(pyrid-
in-4-ylmethyl)pyridin-3-amine;
7-({4-[3-(2-pyridin-3-ylmorpholin-4-yl)pyridin-2-yl]phenoxy}methyl)-1,2,3-
,4-tetrahydro-1,8-naphthyridine;
N-(pyridin-4-ylmethyl)-2-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmeth-
oxy)phenyl]pyridin-3-amine;
2-({4-[3-(3,4-dihydroisoquinolin-2(1H)-yl)pyridin-2-yl]phenoxy}methyl)qui-
noline;
7-{2-[4-(quinolin-2-ylmethoxy)phenyl]pyridin-3-yl}-6,7,8,9-tetrahy-
dropyrido [2,3-b]-1,6-naphthyridine;
6-(2-{4-[(4-methoxy-3,5-dimethylpyridin-2-yl)methoxy]phenyl}pyridin-3-yl)-
-5,6,7,8-tetrahydro-1,6-naphthyridine;
N-ethyl-N-pyridin-3-yl-2-[4-(quinolin-2-ylmethoxy)phenyl]pyridin-3-amine;
2-({4-[3-(2-pyridin-3-ylmorpholin-4-yl)pyridin-2-yl]phenoxy}methyl)quinol-
ine;
4-(2-{3-chloro-5-methoxy-4-[(4-methoxy-3,5-dimethylpyridin-2-yl)metho-
xy]phenyl}pyridin-3-yl)morpholine; 2-({4-[3 -(2,3
-dihydro-1H-pyrrolo[2,3
-c]pyridin-1-yl)pyridin-2-yl]phenoxy}-methyl)quinoline;
6-(2-{4-[(6-methylpyridin-2-yl)methoxy]phenyl}pyridin-3-yl)-3-(trifluorom-
ethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine;
6-(5-fluoro-2-{4-[(4-methoxy-3,5-dimethylpyridin-2-yl)methoxy]phenyl}pyri-
din-3-yl)-5,6,7,8-tetrahydro-1,6-naphthyridine;
4-[2-(4-{[5-(trifluoromethyl)pyridin-2-yl]methoxy}phenyl)pyridin-3-yl]mor-
pholine; 6-{4-[4-(quinolin-2-ylmethoxy)phenyl]pyridin-3-yl}-5 ,6,7,
8-tetrahydro-1,6-naphthyridine ; and
6-{3-[4-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-ylmethoxy)phenyl]pyrazin-2-
-yl}-5,6,7,8-tetrahydro-1,6-naphthyridine; or a pharmaceutically
acceptable salt thereof.
11. A pharmaceutical composition which comprises a pharmaceutically
acceptable carrier and a compound of claim 1 or a pharmaceutically
acceptable salt thereof.
12. (canceled)
13. (canceled)
14. A method for treating a neurological or psychiatric disorder
associated with PDE10 dysfunction in a mammalian patient in need
thereof which comprises administering to the patient a
therapeutically effective amount of a compound of claim 1 or a
pharmaceutically acceptable salt thereof.
15. A method for treating a neurological or psychiatric disorder
associated with striatal hypofunction or basal ganglia dysfunction
in a mammalian patient in need thereof which comprises
administering to the patient a therapeutically effective amount of
a compound of claim 1 or a pharmaceutically acceptable salt
thereof.
16. A method for treating schizophrenia in a mammalian patient in
need thereof which comprises administering to the patient a
therapeutically effective amount of a compound of claim 1 or a
pharmaceutically acceptable salt thereof.
17. A method for treating bipolar disorder in a mammalian patient
in need thereof which comprises administering to the patient a
therapeutically effective amount of a compound of claim 1 or a
pharmaceutically acceptable salt thereof.
18. A method for treating Huntington's disease in a mammalian
patient in need thereof which comprises administering to the
patient a therapeutically effective amount of a compound of claim 1
or a pharmaceutically acceptable salt thereof.
19. A method for enhancing cognition in a mammalian patient in need
thereof which comprises administering to the patient a
therapeutically effective amount of a compound of claim 1 or a
pharmaceutically acceptable salt thereof.
20. A method for treating anxiety in a mammalian patient in need
thereof which comprises administering to the patient a
therapeutically effective amount of a compound of claim 1 or a
pharmaceutically acceptable salt thereof.
Description
FIELD OF THE INVENTION
[0001] The invention relates generally to compounds which act as
inhibitors of the phosphodiesterase (PDE) 10 enzyme, compositions
and therapeutic uses thereof.
BACKGROUND OF THE INVENTION
[0002] Schizophrenia is debilitating disorder affecting the psychic
and motor functions of the brain. It is typically diagnosed in
individuals in their early to mid-twenties and symptoms include
hallucinations and delusions or at the other extreme, anhedonia or
social withdrawal. Across the spectrum, the symptoms are indicative
of cognitive impairment and functional disabilities.
Notwithstanding improvements in antipsychotic treatments, current
therapies, including typical (haloperidol) and atypical (clozapine
or olanzapine) antipsychotics, have been less than acceptable and
result in an extremely high rate of noncomplicance or
discontinuation of medication. Dissatisfaction with therapy is
attributed to lack of efficacy or intolerable and unacceptable side
affects. The side effects have been associated with significant
metabolic, extrapyramidal, prolactic and cardiac adverse events.
See, Lieberman et al., N. Engl. J. Med. (2005) 353:1209-1223.
[0003] While multiple pathways are believed to be involved with the
pathogenesis of schizophrenia leading to psychosis and cognition
deficits, much attention has focused on the role of glutamate/NMDA
dysfunction associated with cyclic guanosine monophasphate (cGMP)
levels and the dopaminergic D2 receptor associated with cyclic
adenosine monophosphate (cAMP). These ubiquitous second messengers
are responsible for altering the function of many intracellular
proteins. Cyclic AMP is thought to regulate the activity of
cAMP-dependent protein kinase (PKA), which in turns phosphorylates
and regulates many types of proteins including ion channels,
enzymes and transcription factors. Similarly, cGMP is also
responsible for downstream regulation of kinases and ion
channels.
[0004] One pathway for affecting the levels of cyclic nucleotides,
such as cAMP and cGMP, is to alter or regulate the enzymes that
degrade these enzymes, known as 3', 5'-cyclic nucleotide specific
phosphodiesterases (PDEs). The PDE superfamily includes twenty one
genes that encode for eleven families of PDEs. These families are
further subdivided based on catalytic domain homology and substrate
specificity and include the 1) cAMP specific, PDE4A-D, 7A and 7B,
and 8A and 8B, 2) cGMP specific, PDE 5A, 6A-C, and 9A, and 3) those
that are dual substrate, PDE 1A-C, 2A, 3A and 3B, 10A, and 11A. The
homology between the families, ranging from 20% to 45% suggests
that it may be possible to develop selective inhibitors for each of
these subtypes.
[0005] The identification of PDE 10 was reported by three groups
independently and was distinguished from other PDEs on the basis of
its amino acid sequence, functional properties, and tissue
distribution (Fujishige et al., J. Biol. Chem. (1999)
274:18438-18445; Loughney et al., Gene (1999) 234: 109-117;
Soderling et al., PNAS, USA (1999) 96: 7071-7076). The PDE10
subtype at present consists of a sole member, PDE10A, having
alternative splice variants at both the N-terminus (three variants)
and C-terminus (two variants), but that does not affect the GAF
domain in the N-terminus or the catalytic site in C-terminus. The
N-terminus splice variants, PDE10A1 and PDE10A2, differ in that the
A2 variant has a PKA phosphorylation site that upon activation,
i.e. PKA phosphorylation in response to elevated cAMP levels,
results in intracellular changes to the localization of the enzyme.
PDE10A is unique relative to other PDE families also having the
conserved GAF domain in that its ligand is cAMP, while for the
other GAF-domain PDEs the ligand is cGMP (Kehler et al., Expert
Opin. Ther. Patents (2007) 17(2): 147-158). PDE10A has limited but
high expression in the brain and testes. The high expression in the
brain and, in particular, the neurons of the striatum, unique to
PDE10, suggests that inhibitors thereto may be well suited from
treating neurological and psychiatric disorders and conditions.
[0006] Inhibition of PDE10 is believed to be useful in the
treatment of schizophrenia and a wide variety of conditions or
disorders that would benefit from increasing levels of cAMP and/or
cGMP within neurons, including a variety neurological, psychotic,
anxiety and/or movement disorders. Accordingly, agents that inhibit
PDE10 and especially PDE10A would be desirable as therapeutics for
neurological and psychiatric disorders.
SUMMARY OF THE INVENTION
[0007] The present invention is directed to aryl aminopyridine
compounds which are useful as therapeutic agents for the treatment
of central nervous system disorders associated with
phosphodiesterase 10 (PDE10). The present invention also relates to
the use of such compounds for treating neurological and psychiatric
disorders, such as schizophrenia, psychosis or Huntington's
disease, and those associated with striatal hypofunction or basal
ganglia dysfunction.
DETAILED DESCRIPTION OF THE INVENTION
[0008] The present invention is directed to compounds of the
formula I:
##STR00001##
[0009] wherein:
[0010] X is --CH-- or N,
[0011] Y is --CH-- or N, and
[0012] Z is --CH-- or N, with the proviso that at least one of X, Y
and Z is N;
[0013] R.sup.1 is selected from the group consisting of: [0014] (1)
hydrogen, [0015] (2) halogen, [0016] (4) C.sub.1-6alkyl, which is
unsubstituted or substituted with halogen, hydroxyl, or phenyl, and
[0017] (5) --O--C.sub.1-6alkyl, which is unsubstituted or
substituted with halogen, hydroxyl or phenyl;
[0018] R.sup.2a, R.sup.2b and R.sup.2c are independently selected
from the group consisting of [0019] (1) hydrogen, [0020] (2)
halogen, [0021] (3) hydroxyl, [0022] (4) C.sub.1-6alkyl, which is
unsubstituted or substituted with halogen, hydroxyl, phenyl or
napthyl, [0023] (5) --O--C.sub.1-6alkyl, which is unsubstituted or
substituted with halogen, hydroxyl or phenyl, [0024] (6) phenyl,
which is unsubstituted or substituted with halogen, hydroxyl,
--O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is unsubstituted or
substituted with fluoro, [0025] (7) heteroaryl, which is
unsubstituted or substituted with halogen, hydroxyl,
--O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is unsubstituted or
substituted with fluoro, [0026] (8) --O---phenyl, which is
unsubstituted or substituted with halogen, hydroxyl,
--O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is unsubstituted or
substituted with fluoro, [0027] (9) --NH--C.sub.1-6alkyl, or
--N(C.sub.1-6alkyl)(C.sub.1-6alkyl) which is unsubstituted or
substituted with halogen, hydroxyl, --O--C.sub.1-6alkyl or
C.sub.1-6alkyl, which is unsubstituted or substituted with fluoro,
[0028] (10) --CO.sub.2H, [0029] (11) --CN, and [0030] (12)
--NO.sub.2, or R.sup.2a and R.sup.2b may be joined together to form
a phenyl, pyridyl or piperidinyl ring, which is unsubstituted or
substituted with R.sup.2c;
[0031] R.sup.3 and R.sup.4 are independently selected from the
group consisting of: [0032] (1) hydrogen, and [0033] (2)
C.sub.1-6alkyl, which is unsubstituted or substituted with
R.sup.14, or R.sup.3 and R.sup.4 may be joined together to form a
heterocyclyl, which is unsubstituted or substituted with halogen,
hydroxyl, phenyl, pyridyl, --O--C.sub.1-6alkyl or C.sub.1-6alkyl,
which is unsubstituted or substituted with halogen, hydroxyl or
phenyl;
[0034] R.sup.14 is selected from the group consisting of: [0035]
(1) hydroxyl, [0036] (2) halogen, [0037] (3) C.sub.1-6alkyl, [0038]
(4) --C.sub.3-6cycloalkyl, [0039] (5) --O--C.sub.1-6alkyl, [0040]
(6) --O(C.dbd.O)--C.sub.1-6alkyl, [0041] (7) .dbd.O, [0042] (8)
--CO.sub.2, [0043] (9) --CO.sub.2--C.sub.1-6alkyl, [0044] (10)
--NH(C.dbd.O)--C.sub.1-6alkyl,
--N(C.sub.1-6alkyl)(C.dbd.O)--C.sub.1-6alkyl,
--NH(C.dbd.O)--O--C.sub.1-6alkyl,
--N(C.sub.1-6alkyl)(C.dbd.O)--O--C.sub.1-6alkyl, which is
unsubstituted or substituted with halogen, hydroxyl,
--O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is unsubstituted or
substituted with fluoro, [0045] (11) --NH--C.sub.1-6alkyl, or
--N(C.sub.1-6alkyl)--C.sub.1-6alkyl, which is unsubstituted or
substituted with halogen, hydroxyl, --O--C.sub.1-6alkyl or
C.sub.1-6alkyl, which is unsubstituted or substituted with fluoro,
[0046] (12) phenyl, which is unsubstituted or substituted with
halogen, hydroxyl, --O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is
unsubstituted or substituted with fluoro, [0047] (13) heteroaryl,
which is unsubstituted or substituted with halogen, hydroxyl,
--O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is unsubstituted or
substituted with fluoro, [0048] (14) heterocyclyl, which is
unsubstituted or substituted with halogen, hydroxyl,
--O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is unsubstituted or
substituted with fluoro, and [0049] (15) --CN;
[0050] or a pharmaceutically acceptable salt thereof.
[0051] An embodiment of the present invention includes compounds of
the formula Ia:
##STR00002##
wherein R.sup.1, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.3 and R.sup.4
are defined herein; or a pharmaceutically acceptable salt
thereof.
[0052] An embodiment of the present invention includes compounds of
the formula Ia':
##STR00003##
wherein R.sup.1, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.3 and R.sup.4
are defined herein; or a pharmaceutically acceptable salt
thereof.
[0053] An embodiment of the present invention includes compounds of
the formula Ia'':
##STR00004##
wherein R.sup.1, R.sup.2a, R.sup.2b, R.sup.2c, R.sup.3 and R.sup.4
are defined herein; or a pharmaceutically acceptable salt
thereof.
[0054] An embodiment of the present invention includes compounds of
the formula Ib:
##STR00005##
wherein R.sup.1, R.sup.2a, R.sup.2b, and R.sup.2c are defined
herein; or a pharmaceutically acceptable salt thereof.
[0055] An embodiment of the present invention includes compounds of
the formula Ib':
##STR00006##
wherein R.sup.1, R.sup.2a, R.sup.2b, and R.sup.2c are defined
herein; or a pharmaceutically acceptable salt thereof.
[0056] An embodiment of the present invention includes compounds of
the formula Ib'':
##STR00007##
wherein R.sup.1, R.sup.2a, R.sup.2b, and R.sup.2c are defined
herein; or a pharmaceutically acceptable salt thereof.
[0057] An embodiment of the present invention includes compounds of
the formula Ic:
##STR00008##
wherein R.sup.1, R.sup.2a, R.sup.2b, and R.sup.2c are defined
herein; or a pharmaceutically acceptable salt thereof.
[0058] An embodiment of the present invention includes compounds of
the formula Ic':
##STR00009##
wherein R.sup.1, R.sup.2a, R.sup.2b, and R.sup.2c are defined
herein; or a pharmaceutically acceptable salt thereof.
[0059] An embodiment of the present invention includes compounds of
the formula Ic'':
##STR00010##
wherein R.sup.1, R.sup.2a, R.sup.2b, and R.sup.2c are defined
herein; or a pharmaceutically acceptable salt thereof.
[0060] An embodiment of the present invention includes compounds of
the formula Id:
##STR00011##
wherein R.sup.1, R.sup.2a, R.sup.2b, and R.sup.2c are defined
herein; or a pharmaceutically acceptable salt thereof.
[0061] An embodiment of the present invention includes compounds of
the formula Id':
##STR00012##
wherein R.sup.1, R.sup.2a, R.sup.2b, and R.sup.2c are defined
herein; or a pharmaceutically acceptable salt thereof.
[0062] An embodiment of the present invention includes compounds of
the formula Id'':
##STR00013##
wherein R.sup.1, R.sup.2a, R.sup.2b, and R.sup.2c are defined
herein; or a pharmaceutically acceptable salt thereof.
[0063] An embodiment of the present invention includes compounds
wherein X is N, Y is --CH--, and Z is --CH--. An embodiment of the
present invention includes compounds wherein X is X is --CH--, Y is
--N, and Z is --CH--. An embodiment of the present invention
includes compounds wherein X is --CH--, Y is --CH--, and Z is N. An
embodiment of the present invention includes compounds wherein X is
N, Y is --CH--, and Z is N.
[0064] An embodiment of the present invention includes compounds
wherein R.sup.1 is selected from the group consisting of: [0065]
(1) hydrogen, and [0066] (2) halogen.
[0067] An embodiment of the present invention includes compounds
wherein R.sup.1 is selected from the group consisting of: [0068]
(1) hydrogen, and [0069] (2) fluoro.
[0070] An embodiment of the present invention includes compounds
wherein R.sup.1 is hydrogen.
[0071] An embodiment of the present invention includes compounds
wherein R.sup.2a, R.sup.2b and R.sup.2c are independently selected
from the group consisting of: [0072] (1) hydrogen, [0073] (2)
halogen, [0074] (3) hydroxyl, [0075] (4) C.sub.1-6alkyl, which is
unsubstituted or substituted with halogen, hydroxyl, phenyl or
napthyl, [0076] (5) --O--C.sub.1-6alkyl, which is unsubstituted or
substituted with halogen, hydroxyl or phenyl, [0077] (6) phenyl,
which is unsubstituted or substituted with halogen, hydroxyl,
--O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is unsubstituted or
substituted with fluoro, [0078] (7) heteroaryl, which is
unsubstituted or substituted with halogen, hydroxyl,
--O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is unsubstituted or
substituted with fluoro, [0079] (8) --O-phenyl, which is
unsubstituted or substituted with halogen, hydroxyl,
--O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is unsubstituted or
substituted with fluoro, [0080] (9) --NH--C.sub.1-6alkyl, or
--N(C.sub.1-6alkyl)(C.sub.1-6alkyl), which is unsubstituted or
substituted with halogen, hydroxyl, --O--C.sub.1-6alkyl or
C.sub.1-6alkyl, which is unsubstituted or substituted with fluoro,
[0081] (10) --CO.sub.2H, [0082] (11) --CN, and [0083] (12)
--NO.sub.2, or R.sup.2a and R.sup.2b may be joined together to form
a phenyl, pyridyl or piperidinyl ring, which is unsubstituted or
substituted with R.sup.2c.
[0084] An embodiment of the present invention includes compounds
wherein R.sup.2a, R.sup.2b and R.sup.2c are independently selected
from the group consisting of: [0085] (1) hydrogen, [0086] (2)
halogen, [0087] (3) hydroxyl, [0088] (4) C.sub.1-6alkyl, which is
unsubstituted or substituted with halogen, hydroxyl or phenyl or
napthyl, and [0089] (5) --O--C.sub.1-6alkyl, which is unsubstituted
or substituted with halogen, hydroxyl or phenyl.
[0090] An embodiment of the present invention includes compounds
wherein R.sup.2a, R.sup.2b and R.sup.2c are independently selected
from the group consisting of: [0091] (1) hydrogen, [0092] (2)
methyl, [0093] (3) ethyl, [0094] (4) trifluromethyl, and [0095] (5)
methoxy.
[0096] An embodiment of the present invention includes compounds
wherein R.sup.2a and R.sup.2b are joined together to form a phenyl,
pyridyl or piperidinyl ring.
[0097] An embodiment of the present invention includes compounds
wherein R.sup.3 and R.sup.4 are independently selected from the
group consisting of [0098] (1) hydrogen, and [0099] (2)
C.sub.1-6alkyl, which is unsubstituted or substituted with
R.sup.14, or R.sup.3 and R.sup.4 may be joined together to form a
heterocyclyl, which is unsubstituted or substituted with halogen,
hydroxyl, --O--C.sub.1-6alkyl or C.sub.1-6alkyl, which is
unsubstituted or substituted with halogen, hydroxyl or phenyl.
[0100] An embodiment of the present invention includes compounds
wherein R.sup.3 and R.sup.4 are joined together to form a
pyrrolopyridinyl, tetrahydronapthyridinyl,
tetrahydropryido-napthyridinyl, or morpholinyl ring, which is
unsubstituted or substituted with a substituent selected from the
group consisting of: [0101] (1) halogen, [0102] (2) hydroxyl,
[0103] (3) pyridyl, [0104] (4) C.sub.1-6alkyl, which is
unsubstituted or substituted with halogen, hydroxyl or phenyl, and
[0105] (5) --O--C.sub.1-6alkyl, which is unsubstituted or
substituted with halogen, hydroxyl or phenyl.
[0106] An embodiment of the present invention includes compounds
wherein R.sup.3 and R.sup.4 are joined together to form a
tetrahydronapthyridinyl ring. An embodiment of the present
invention includes compounds wherein R.sup.3 and R.sup.4 are joined
together to form a morpholinyl ring.
[0107] Specific embodiments of the present invention include a
compound which is selected from the group consisting of the subject
compounds of the Examples herein and pharmaceutically acceptable
salts thereof and individual enantiomers and diastereomers
thereof.
[0108] As appreciated by those of skill in the art, halogen or halo
as used herein are intended to include fluorine, chlorine, bromine
and iodine. Similarly, "alkyl", as well as other groups having the
prefix "alk", such as alkoxy, alkanoyl, means carbon chains which
may be linear or branched or combinations thereof. C.sub.1-6, as in
C.sub.1-6alkyl is defined to identify the group as having 1, 2, 3,
4, 5 or 6 carbons in a linear or branched arrangement, such as
methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl,
tert-butyl, pentyl, hexyl, and the like. "Alkylene" means a
straight or branched chain of carbon atoms with a group substituted
at both ends, such as --CH.sub.2CH.sub.2-- and
--CH.sub.2CH.sub.2CH.sub.2--. "Alkenyl" means a carbon chain which
contains at least one carbon-carbon double bond, and which may be
linear or branched or combinations thereof such that
C.sub.2-6alkenyl is defined to identify the group as having 2, 3,
4, 5 or 6 carbons which incorporates at least one double bond,
which may be in a E- or a Z- arrangement, including vinyl, allyl,
isopropenyl, pentenyl, hexenyl, heptenyl, 1-propenyl, 2-butenyl,
2-methyl-2-butenyl, and the like. "Alkynyl" means a carbon chain
which contains at least one carbon-carbon triple bond, and which
may be linear or branched or combinations thereof, such as ethynyl,
propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.
"Cycloalkyl" means a mono-, bi- or tri-cyclic structure, optionally
combined with linear or branched structures, having the indicated
number of carbon atoms, such as cyclopropyl, cyclopentyl,
cycloheptyl, adamantyl, cyclododecylmethyl, 2-ethyl-1-
bicyclo[4.4.0]decyl, and the like. "Alkoxy" means an alkoxy group
of a straight or branched chain having the indicated number of
carbon atoms. C.sub.1-6alkoxy, for example, includes methoxy,
ethoxy, propoxy, isopropoxy, and the like. The term "heterocyclyl"
as used herein includes both unsaturated heterocyclic moieties
comprising a mono- or bicyclic aromatic rings with at least one
ring containing a heteroatom selected from N, O and S, and each
ring containing 5 or 6 atoms (i.e. "heteroaryl") and saturated
heterocyclic moieties comprising mono- or bicyclic saturated rings
with at least one ring containing a heteroatom selected from N, O
and S, and each ring containing 3, 5 or 6 atoms. Examples of
"heteroaryl" include benzoimidazolyl, benzimidazolonyl,
benzofuranyl, benzofurazanyl, benzopyrazolyl, benzothiazolyl,
benzotriazolyl, benzothiophenyl, benzoxazepin, benzoxazolyl,
carbazolyl, carbolinyl, cinnolinyl, furanyl, furo(2,3-b)pyridyl,
imidazolyl, indolinyl, indolyl, dihydroindolyl, indolazinyl,
indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl,
isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline,
isoxazoline, oxetanyl, pyrazinyl, pyrazolyl, pyridazinyl,
pyridopyridinyl, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl,
pyrrolopyridinyl, quinazolinyl, quinolyl, quinoxalinyl,
tetrahydronapthyridinyl, tetrahydropryidonapthyridinyl,
tetrahydroquinoxalinyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl,
thiazolyl, thienyl, triazolyl, and N-oxides thereof. Examples of
saturated heterocyclic moieties ("saturated heterocycle") include
azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl,
piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl,
tetrahydrofuranyl, thiomorpholinyl, and tetrahydrothienyl, and
N-oxides thereof.
[0109] A group which is designated as being substituted with
substituents may be substituted with multiple numbers of such
substituents. A group which is designated as being independently
substituted with substituents may be independently substituted with
multiple numbers of such substituents.
[0110] The compounds of the present invention may contain one or
more stereogenic centers and can thus occur as racemates, racemic
mixtures, single enantiomers, diastereomeric mixtures and
individual diastereomers. Additional asymmetric centers may be
present depending upon the nature of the various substituents on
the molecule. Each such asymmetric center will independently
produce two optical isomers and it is intended that all of the
possible optical isomers and diastereomers in mixtures and as pure
or partially purified compounds are included within the ambit of
this invention. Any formulas, structures or names of compounds
described in this specification that do not specify a particular
stereochemistry are meant to encompass any and all existing isomers
as described above and mixtures thereof in any proportion. When
stereochemistry is specified, the invention is meant to encompass
that particular isomer in pure form or as part of a mixture with
other isomers in any proportion.
[0111] The independent syntheses of these diastereomers or their
chromatographic separations may be achieved as known in the art by
appropriate modification of the methodology disclosed herein. Their
absolute stereochemistry may be determined by the x-ray
crystallography of crystalline products or crystalline
intermediates which are derivatized, if necessary, with a reagent
containing an asymmetric center of known absolute configuration. If
desired, racemic mixtures of the compounds may be separated so that
the individual enantiomers are isolated. The separation can be
carried out by methods well known in the art, such as the coupling
of a racemic mixture of compounds to an enantiomerically pure
compound to form a diastereomeric mixture, followed by separation
of the individual diastereomers by standard methods, such as
fractional crystallization or chromatography. The coupling reaction
is often the formation of salts using an enantiomerically pure acid
or base. The diasteromeric derivatives may then be converted to the
pure enantiomers by cleavage of the added chiral residue. The
racemic mixture of the compounds can also be separated directly by
chromatographic methods utilizing chiral stationary phases, which
methods are well known in the art. Alternatively, any enantiomer of
a compound may be obtained by stereoselective synthesis using
optically pure starting materials or reagents of known
configuration by methods well known in the art.
[0112] In the compounds of generic formula I, the atoms may exhibit
their natural isotopic abundances, or one or more of the atoms may
be artificially enriched in a particular isotope having the same
atomic number, but an atomic mass or mass number different from the
atomic mass or mass number predominantly found in nature. The
present invention is meant to include all suitable isotopic
variations of the compounds of generic Formula I. For example,
different isotopic forms of hydrogen (H) include protium (.sup.1H)
and deuterium (.sup.2H). Protium is the predominant hydrogen
isotope found in nature. Enriching for deuterium may afford certain
therapeutic advantages, such as increasing in vivo half-life or
reducing dosage requirements, or may provide a compound useful as a
standard for characterization of biological samples.
Isotopically-enriched compounds within generic Formula I can be
prepared without undue experimentation by conventional techniques
well known to those skilled in the art or by processes analogous to
those described in the Schemes and Examples herein using
appropriate isotopically-enriched reagents and/or
intermediates.
[0113] It will be understood that, as used herein, references to
the compounds of present invention are meant to also include the
pharmaceutically acceptable salts, and also salts that are not
pharmaceutically acceptable when they are used as precursors to the
free compounds or in other synthetic manipulations. The compounds
of the present invention may be administered in the form of a
pharmaceutically acceptable salt. The term "pharmaceutically
acceptable salts" refers to salts prepared from pharmaceutically
acceptable non-toxic bases or acids. When the compound of the
present invention is acidic, its corresponding salt can be
conveniently prepared from pharmaceutically acceptable non-toxic
bases, including inorganic bases and organic bases. Salts derived
from such inorganic bases include aluminum, ammonium, calcium,
cupric, cuprous, ferric, ferrous, lithium, magnesium, manganic,
manganous, potassium, sodium, zinc and the like salts. Particular
embodiments include the ammonium, calcium, magnesium, potassium,
and sodium salts. Salts in the solid form may exist in more than
one crystal structure, and may also be in the form of hydrates.
Salts derived from pharmaceutically acceptable organic non-toxic
bases include salts of primary, secondary, and tertiary amines,
substituted amines including naturally occurring substituted
amines, cyclic amines, and basic ion exchange resins, such as
arginine, betaine, caffeine, choline,
N,N'-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol,
2-dimethylamino-ethanol, ethanolamine, ethylenediamine,
N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,
histidine, hydrabamine, isopropylamine, lysine, methylglucamine,
morpholine, piperazine, piperidine, polyamine resins, procaine,
purines, theobromine, triethylamine, trimethylamine,
tripropylamine, tromethamine, and the like. When the compound of
the present invention is basic, salts may be prepared from
pharmaceutically acceptable non-toxic acids, including inorganic
and organic acids. Such acids include acetic, benzenesulfonic,
benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric,
gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,
maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic,
pantothenic, phosphoric, succinic, sulfuric, tartaric,
p-toluenesulfonic acid, and the like. Particular embodiments
citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric,
fumaric, and tartaric acids. It will be understood that, as used
herein, references to the compounds of the present invention are
meant to also include the pharmaceutically acceptable salts.
[0114] Exemplifying the invention are the specific compounds
disclosed in the Examples and herein. The subject compounds are
useful in a method of treating a neurological or psychiatric
disorder associated with PDE10 dysfunction in a patient such as a
mammal in need of such inhibition comprising the administration of
an effective amount of the compound. In addition to primates,
especially humans, a variety of other mammals can be treated
according to the method of the present invention. The subject
compounds are useful in a method of inhibiting PDE10 activity in a
patient such as a mammal in need of such inhibition comprising the
administration of an effective amount of the compound. The subject
compounds are also useful for treating a neurological or
psychiatric disorder associated with striatal hypofunction or basal
ganglia dysfunction in a mammalian patient in need thereof. In
addition to primates, especially humans, a variety of other mammals
can be treated according to the method of the present
invention.
[0115] The present invention is directed to a compound of the
present invention or a pharmaceutically acceptable salt thereof for
use in medicine. The present invention is further directed to a use
of a compound of the present invention or a pharmaceutically
acceptable salt thereof for the manufacture of a medicament for
treating a neurological or psychiatric disorder associated with
PDE10 dysfunction in a mammalian patient in need thereof. The
present invention is further directed to a use of a compound of the
present invention or a pharmaceutically acceptable salt thereof for
the manufacture of a medicament for treating a neurological or
psychiatric disorder associated with striatal hypofunction or basal
ganglia dysfunction in a mammalian patient in need thereof.
[0116] "Treating" or "treatment of" a disease state includes: 1)
preventing the disease state, i.e. causing the clinical symptoms of
the disease state not to develop in a subject that may be exposed
to or predisposed to the disease state, but does not yet experience
or display symptoms of the disease state; 2) inhibiting the disease
state, i.e., arresting the development of the disease state or its
clinical symptoms; 3) or relieving the disease state, i.e., causing
temporary or permanent regression of the disease state or its
clinical symptoms.
[0117] The subject treated in the present methods is generally a
mammal, in particular, a human being, male or female, in whom
therapy is desired. The term "therapeutically effective amount"
means the amount of the subject compound that will elicit the
biological or medical response of a tissue, system, animal or human
that is being sought by the researcher, veterinarian, medical
doctor or other clinician. It is recognized that one skilled in the
art may affect the neurological and psychiatric disorders by
treating a patient presently afflicted with the disorders or by
prophylactically treating a patient afflicted with such disorders
with an effective amount of the compound of the present invention.
As used herein, the terms "treatment" and "treating" refer to all
processes wherein there may be a slowing, interrupting, arresting,
controlling, or stopping of the progression of the neurological and
psychiatric disorders described herein, but does not necessarily
indicate a total elimination of all disorder symptoms, as well as
the prophylactic therapy to retard the progression or reduce the
risk of the noted conditions, particularly in a patient who is
predisposed to such disease or disorder.
[0118] Applicants propose that inhibitors of PDE10 and, in
particular inhibitors of PDE10A, will provide therapeutic benefit
to those individuals suffering from psychiatric and cognitive
disorders. The unique and exclusive distribution of PDE10A in the
medium spiny projection neurons of the striatum, which form the
principle site for cortical and dopaminergic input within basal
ganglia, suggests that it may be possible and desirable to identify
inhibitors of PDE10 to ameliorate or eliminate unwanted cellular
signaling within this site. Without wishing to be bound by any
theory, Applicants believe that inhibition of PDE 10A in the
striatum will result in increased cAMP/cGMP signaling and striatal
output, which has the potential to restore behavioral inhibition
that is impaired in cognitive disease such as schizophrenia.
Regulation and integration of glutamatergic and dopaminergic inputs
will enhance cognitive behavior, while suppressing or reducing
unwanted behavior. Thus, in one embodiment, compounds of the
invention provide a method for treating or ameliorating diseases or
conditions in which striatal hypofunction is a prominent feature or
ones in which basal ganglia dysfunction plays a role, such as,
Parkinson's disease, Huntington's disease, schizophrenia,
obsessive-compulsive disorders, addiction and psychosis. Other
conditions for which the inhibitors described herein may have a
desirable and useful effect include those requiring a reduction in
activity and reduced response to psychomotor stimulants or where it
would be desirable to reduce conditional avoidance responses, which
is often predictive of clinical antipsychotic activity.
[0119] As used herein, the term "selective PDE 10 inhibitor" refers
to an organic molecule that effectively inhibits an enzyme from the
PDE10 family to a greater extent than enzymes from the PDE 1-9 or
PDE11 families. In one embodiment, a selective PDE10 inhibitor is
an organic molecule having a Ki for inhibition of PDE10 that is
less than or about one-tenth that for a substance that is an
inhibitor for another PDE enzyme. In other words, the organic
molecule inhibits PDE10 activity to the same degree at a
concentration of about one-tenth or less than the concentration
required for any other PDE enzyme. Preferably, a selective PDE10
inhibitor is an organic molecule, having a Ki for inhibition of
PDE10 that is less than or about one-hundredth that for a substance
that is an inhibitor for another PDE enzyme. In other words, the
organic molecule inhibits PDE10 activity to the same degree at a
concentration of about one-hundredth or less than the concentration
required for any other PDE enzyme. A selective PDE10 inhibitor can
be-identified, for example, by comparing the ability of an organic
molecule to inhibit PDE 10 activity to its ability to inhibit PDE
enzymes from the other PDE families. For example, an organic
molecule may be assayed for its ability to inhibit PDE 10 activity,
as well as PDE1A, PDE1B, PDE1C, PDE2A, PDE3A, PDE3B, PDE4A, PDE4B,
PDE4C, PDE4D, PDE5A, PDE6A, PDE6B, PDE6C, PDE7A, PDE7B, PDE8A,
PDE8B, PDE9A, and/or PDE11A.
[0120] Phosphodiesterase enzymes including PDE10 have been
implicated in a wide range of biological functions. This has
suggested a potential role for these enzymes in a variety of
disease processes in humans or other species. The compounds of the
present invention have utility in treating a variety of
neurological and psychiatric disorders.
[0121] In a specific embodiment, compounds of the present invention
provide a method for treating schizophrenia or psychosis comprising
administering to a patient in need thereof an effective amount of a
compound of the present invention. The Diagnostic and Statistical
Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric
Association, Washington DC) provides a diagnostic tool that
includes paranoid, disorganized, catatonic or undifferentiated
schizophrenia and substance-induced psychotic disorders. As used
herein, the term "schizophrenia or psychosis" includes the
diagnosis and classification of these mental disorders as described
in DSM-IV-TR and the term is intended to include similar disorders
described in other sources. Disorders and conditions encompassed
herein include, but are not limited to, conditions or diseases such
as schizophrenia or psychosis, including schizophrenia (paranoid,
disorganized, catatonic, undifferentiated, or residual type),
schizophreniform disorder, schizoaffective disorder, for example of
the delusional type or the depressive type, delusional disorder,
psychotic disorder, brief psychotic disorder, shared psychotic
disorder, psychotic disorder due to a general medical condition and
substance-induced or drug-induced (for example psychosis induced by
alcohol, amphetamine, cannabis, cocaine, hallucinogens, inhalants,
opioids, phencyclidine, ketamine and other dissociative
anaesthetics, and other psychostimulants), psychosispsychotic
disorder, psychosis associated with affective disorders, brief
reactive psychosis, schizoaffective psychosis,
"schizophrenia-spectrum" disorders such as schizoid or schizotypal
personality disorders, personality disorder of the paranoid type,
personality disorder of the schizoid type, illness associated with
psychosis (such as major depression, manic depressive (bipolar)
disorder, Alzheimer's disease and post-traumatic stress syndrome),
including both the positive and the negative symptoms of
schizophrenia and other psychoses.
[0122] In another specific embodiment, the compounds of the present
invention provide a method for treating cognitive disorders
comprising administering to a patient in need thereof an effective
amount of a compound of the present invention. The DSM-IV-TR also
provides a diagnostic tool that includes cognitive disorders
including dementia, delirium, amnestic disorders and age-related
cognitive decline. As used herein, the term "cognitive disorders"
includes the diagnosis and classification of these disorders as
described in DSM-IV-TR and the term is intended to include similar
disorders described in other sources. Disorders and conditions
encompassed herein include, but are not limited to, disorders that
comprise as a symptom a deficiency in attention and/or cognition,
such as dementia (associated with Alzheimer's disease, ischemia,
multi-infarct dementia, trauma, intracranial tumors, cerebral
trauma, vascular problems or stroke, alcoholic dementia or other
drug-related dementia, AIDS, HIV disease, Parkinson's disease,
Huntington's disease, Pick's disease, Creutzfeldt Jacob disease,
perinatal hypoxia, other general medical conditions or substance
abuse), Alzheimer's disease, multi-infarct dementia, AIDS-related
dementia, and Fronto temperal dementia, delirium, amnestic
disorders or age related cognitive decline.
[0123] In another specific embodiment, compounds of the present
invention provide a method for treating anxiety disorders
comprising administering to a patient in need thereof an effective
amount of a compound of the present invention. The DSM-IV-TR also
provides a diagnostic tool that includes anxiety disorders as
generalized anxiety disorder, obsessive-compulsive disorder and
panic attack. As used herein, the term "anxiety disorders" includes
the diagnosis and classification of these mental disorders as
described in DSM-IV-TR and the term is intended to include similar
disorders described in other sources. Disorders and conditions
encompassed herein include, but are not limited to, anxiety
disorders such as, acute stress disorder, agoraphobia, generalized
anxiety disorder, obsessive-compulsive disorder, panic attack,
panic disorder, post-traumatic stress disorder, separation anxiety
disorder, social phobia, specific phobia, substance-induced anxiety
disorder and anxiety due to a general medical condition.
[0124] In another specific embodiment, compounds of the present
invention provide a method for treating substance-related disorders
and addictive behaviors comprising administering to a patient in
need thereof an effective amount of a compound of the present
invention. The DSM-IV-TR also provides a diagnostic tool that
includes persisting dementia, persisting amnestic disorder,
psychotic disorder or anxiety disorder induced by substance abuse,
and tolerance of, dependence on or withdrawal from substances of
abuse. As used herein, the term "substance-related disorders and
addictive behaviors" includes the diagnosis and classification of
these mental disorders as described in DSM-IV-TR and the term is
intended to include similar disorders described in other sources.
Disorders and conditions encompassed herein include, but are not
limited to, substance-related disorders and addictive behaviors,
such as substance-induced delirium, persisting dementia, persisting
amnestic disorder, psychotic disorder or anxiety disorder, drug
addiction, tolerance, and dependence or withdrawal from substances
including alcohol, amphetamines, cannabis, cocaine, hallucinogens,
inhalants, nicotine, opioids, phencyclidine, sedatives, hypnotics
or anxiolytics.
[0125] In another specific embodiment, compounds of the present
invention provide a method for treating obesity or eating disorders
associated with excessive food intake, and complications associated
therewith, comprising administering to a patient in need thereof an
effective amount of a compound of the present invention. At
present, obesity is included in the tenth edition of the
International Classification of Diseases and Related Health
Problems (ICD-10) (1992 World Health Organization) as a general
medical condition. The DSM-IV-TR also provides a diagnostic tool
that includes obesity in the presence of psychological factors
affecting medical condition. As used herein, the term "obesity or
eating disorders associated with excessive food intake" includes
the diagnosis and classification of these medical conditions and
disorders described in ICD-10 and DSM-IV-TR and the term is
intended to include similar disorders described in other sources.
Disorders and conditions encompassed herein include, but are not
limited to, obesity, bulimia nervosa and compulsive eating
disorders.
[0126] In another specific embodiment, compounds of the present
invention provide a method for treating mood and depressive
disorders comprising administering to a patient in need thereof an
effective amount of a compound of the present invention. As used
herein, the term "mood and depressive disorders" includes the
diagnosis and classification of these medical conditions and
disorders described in the DSM-FV-TR and the term is intended to
include similar disorders described in other sources. Disorders and
conditions encompassed herein include, but are not limited to,
bipolar disorders, mood disorders including depressive disorders,
major depressive episode of the mild, moderate or severe type, a
manic or mixed mood episode, a hypomanic mood episode, a depressive
episode with atypical features, a depressive episode with
melancholic features, a depressive episode with catatonic features,
a mood episode with postpartum onset, post-stroke depression; major
depressive disorder, dysthymic disorder, minor depressive disorder,
premenstrual dysphoric disorder, post-psychotic depressive disorder
of schizophrenia, a major depressive disorder superimposed on a
psychotic disorder such as delusional disorder or schizophrenia, a
bipolar disorder, for example, bipolar I disorder, bipolar II
disorder, cyclothymic disorder, depression including unipolar
depression, seasonal depression and post-partum depression,
premenstrual syndrome (PMS) and premenstrual dysphoric disorder
(PDD), mood disorders due to a general medical condition, and
substance-induced mood disorders.
[0127] In another specific embodiment, compounds of the present
invention provide a method for treating pain comprising
administering to a patient in need thereof an effective amount of a
compound of the present invention. Particular pain embodiments are
bone and joint pain (osteoarthritis), repetitive motion pain,
dental pain, cancer pain, myofascial pain (muscular injury,
fibromyalgia), perioperative pain (general surgery, gynecological),
chronic pain and neuropathic pain.
[0128] In other specific embodiments, compounds of the invention
provide methods for treating other types of cognitive, learning and
mental related disorders including, but not limited to, learning
disorders, such as a reading disorder, a mathematics disorder, or a
disorder of written expression, attention-deficit/hyperactivity
disorder, age-related cognitive decline, pervasive developmental
disorder including autistic disorder, attention disorders such as
attention-deficit hyperactivity disorder (ADHD) and conduct
disorder; an NMDA receptor-related disorder, such as autism,
depression, benign forgetfulness, childhood learning disorders and
closed head injury; a neurodegenerative disorder or condition, such
as neurodegeneration associated with cerebral trauma, stroke,
cerebral infarct, epileptic seizure, neurotoxin poisoning, or
hypoglycemia-induced neurodegeneration; multi-system atrophy;
movement disorders, such as akinesias and akinetic-rigid syndromes
(including, Parkinson's disease, drug-induced parkinsonism,
post-encephalitic parkinsonism, progressive supranuclear palsy,
multiple system atrophy, corticobasal degeneration,
parkinsonism-ALS dementia complex and basal ganglia calcification),
medication-induced parkinsonism (such as, neuroleptic-induced
parkinsonism, neuroleptic malignant syndrome, neuroleptic-induced
acute dystonia, neuroleptic-induced acute akathisia,
neuroleptic-induced tardive dyskinesia and medication-induced
postural tremor), Huntington's disease, dyskinesia associated with
dopamine agonist therapy, Gilles de la Tourette's syndrome,
epilepsy, muscular spasms and disorders associated with muscular
spasticity or weakness including tremors; dyskinesias, including
tremor (such as, rest tremor, postural tremor, intention tremor and
essential tremor), restless leg syndrome, chorea (such as
Sydenham's chorea, Huntington's disease, benign hereditary chorea,
neuroacanthocytosis, symptomatic chorea, drug-induced chorea and
hemiballism), myoclonus (including, generalised myoclonus and focal
myoclonus), tics (including, simple tics, complex tics and
symptomatic tics), dystonia (including, generalised, iodiopathic,
drug-induced, symptomatic, paroxymal, and focal (such as
blepharospasm, oromandibular, spasmodic, spasmodic torticollis,
axial dystonia, hemiplegic and dystonic writer's cramp)); urinary
incontinence; neuronal damage (including ocular damage, retinopathy
or macular degeneration of the eye, tinnitus, hearing impairment
and loss, and brain edema); emesis; and sleep disorders, including
insomnia and narcolepsy.
[0129] Of the disorders above, the treatment of schizophrenia,
bipolar disorder, depression, including unipolar depression,
seasonal depression and post-partum depression, premenstrual
syndrome (PMS) and premenstrual dysphoric disorder (PDD), learning
disorders, pervasive developmental disorders, including autistic
disorder, attention disorders including
Attention-Deficit/Hyperactivity Disorder, autism, tic disorders
including Tourette's disorder, anxiety disorders including phobia
and post traumatic stress disorder, cognitive disorders associated
with dementia, AIDS dementia, Alzheimer's, Parkinson's,
Huntington's disease, spasticity, myoclonus, muscle spasm, tinnitus
and hearing impairment and loss are of particular importance.
[0130] The activity of the compounds in accordance with the present
invention as PDE10 inhibitors may be readily determined without
undue experimentation using a fluorescence polarization (FP)
methodology that is well known in the art (Huang, W., et al., J.
Biomol Screen, 2002, 7: 215). In particular, the compounds of the
following examples had activity in reference assays by exhibiting
the ability to inhibit the hydrolysis of the phosphosphate ester
bond of a cyclic nucleotide. Any compound exhibiting a Ki
(inhibitory constant) below 1 .mu.M would be considered a PDE10
inhibitor as defined herein.
[0131] In a typical experiment the PDE10 inhibitory activity of the
compounds of the present invention was determined in accordance
with the following experimental method. PDE10A2 was amplified from
human fetal brain cDNA (Clontech, Mountain View, Calif.) using a
forward primer corresponding to nucleotides 56-77 of human PDE10A2
(Accession No. AF127480, Genbank Identifier 4894716), containing a
Kozak consensus sequence, and a reverse primer corresponding to
nucleotides 2406-2413 of human PDE10A2 (Accession No. AF127480,
Genbank Identifier 4894716). Amplification with Easy-A polymerase
(Stratagene, La Jolla, Calif.) was 95.degree. C. for 2 minutes
followed by thirty three cycles of 95.degree. C. for 40 seconds,
55.degree. C. for 30 seconds, and 72.degree. C. for 2 minutes 48
seconds. Final extension was 72.degree. C. for 7 minutes. The PCR
product was TA cloned into pcDNA3.2-TOPO (Invitrogen, Carlsbad,
Calif.) according to standard protocol. AD293 cells with 70-80%
confluency were transiently transfected with human
PDE10A2/pcDNA3.2-TOPO using Lipofectamine 2000 according to
manufacturer specifications (Invitrogen, Carlsbad, Calif.). Cells
were harvested 48 hours post-transfection and lysed by sonication
(setting 3, 10.times.5 sec pulses) in a buffer containing 20 mM
HEPES, 1 mM EDTA and protease inhibitor cocktail (Roche). Lysate
was collected by centrifugation at 75,000 .times.g for 20 minutes.
Supernatant containing the cytoplasmic fraction was used for
evaluation of PDE10A2 activity. The fluorescence polarization assay
for cyclic nucleotide phosphodiesterases was performed using an
IMAP.RTM. FP kit supplied by Molecular Devices, Sunnyvale, Calif.
(product # R8139). IMAP.RTM. technology has been applied previously
to phosphodiesterase assays (Huang, W., et al., J. Biomol Screen,
2002, 7: 215). Assays were performed at room temperature in
384-well microtiter plates with an incubation volume of 20.2 .mu.L.
Solutions of test compounds were prepared in DMSO and serially
diluted with DMSO to yield 8 .mu.L of each of 10 solutions
differing by 3-fold in concentration, at 32 serial dilutions per
plate. 100% inhibition is determined using a known PDE10 inhibitor,
which can be any compound that is present at 5,000 times its Ki
value in the assay described as follows, such as papaverine (see
Siuciak, et al. Neuropharmacology (2006) 51:386-396; Becker, et al.
Behav Brain Res (2008) 186(2):155-60; Threlfell, et al., J
Pharmacol Exp Ther (2009) 328(3):785-795),
2-{4-[pyridin-4-yl-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]phenoxymethyl-
}quinoline succinic acid or
2-[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)-phenoxymethyl]quinoline
succinic acid (see Schmidt, et al. J Pharmacol Exp Ther (2008)
325:681-690; Threlfell, et al., J Pharmacol Exp Ther (2009) 328(3):
785-795). 0% of inhibition is determined by using DMSO (1% final
concentrations). A Labcyte Echo 555 (Labcyte, Sunnyvale, Calif.) is
used to dispense 200 nL from each well-of-the titration plate to
the 384 well assay plate. A solution of enzyme (1/1600 dilution
from aliquots; sufficient to produce 20% substrate conversion) and
a separate solution of FAM-labeled cAMP PDE from Molecular Devices
(product # R7506), at a final concentration of 50 nM are made in
the assay buffer (10 mM Iris HCl, pH 7.2, 10 mM MgCl.sub.2, 0.05%
NaN.sub.3 0.01% Tween-20, and 1 mM DTT). The enzyme and the
substrate are then added to the assay plates in two consecutive
additions of 10 .mu.L, and then shaken to mix. The reaction is
allowed to proceed at room temperature for 30 minutes. A binding
solution is then made from the kit components, comprised of 80%
Solution A, 20% Solution B and binding reagent at a volume of 1/600
the total binding solution. The enzymatic reaction is stopped by
addition of 60 .mu.L of the binding solution to each well of the
assay plates and the plates are sealed and shaken for 10 seconds.
The plate was incubated at room temperature for at least one hour
prior to determining the fluorescence polarization (FP). The
parallel and perpendicular fluorescence of each well of the plate
was measured using a Perkin Elmer EnVision.TM. plate reader
(Waltham, Mass.).
[0132] Fluorescence polarization (mP) was calculated from the
parallel (S) and perpendicular (P) fluorescence of each sample well
and the analogous values for the median control well, containing
only substrate (So and Po), using the following equation:
Polarization (mP)=1000*(S/So-P/Po)/(S/So+P/Po).
[0133] Dose-inhibition profiles for each compound were
characterized by fitting the mP data to a four-parameter equation
given below. The apparent inhibition constant (K.sub.I), the
maximum inhibition at the low plateau relative to "100% Inhibition
Control" (Imax; e.g. 1=22 same as this control), the minimum
inhibition at the high plateau relative to the "0% Inhibition
Control" (Imin, e.g. 0=> same as the no drug control) and the
Hill slope (nH) are determined by a non-linear least squares
fitting of the mP values as a function of dose of the compound
using an in-house software based on the procedures described by
Mosser et al., JALA, 2003, 8: 54-63, using the following
equation:
mP = ( 0 % mP - 100 % mP ) ( Imax - Imin ) 1 + [ [ Drug ] ( 10 - pK
1 ( 1 + [ Substrate ] K M ) ] nH + 100 % mP + ( 0 % mP - 100 % mP )
( 1 - Imax ) ##EQU00001##
[0134] The median signal of the "0% inhibition controls" (0% mP)
and the median signal of the "100% inhibition controls" (100% mP)
are constants determined from the controls located in columns 1-2
and 23-24 of each assay plate. An apparent (K.sub.m) for
PAM-labeled cAMP of 150 nM was determined in separate experiments
through simultaneous variation of substrate and selected drug
concentrations.
[0135] Selectivity for PDE10, as compared to other PDE families,
was assessed using the IMAP.RTM. technology. Rhesus PDE2A3 and
Human PDE10A2 enzyme was prepared from cytosolic fractions of
transiently transfected HEK cells. All other PDE's were GST Tag
human enzyme expressed in insect cells and were obtained from BPS
Bioscience (San Diego, Calif.): PDE1A (Cat# 60010), PDE3A (Cat#
60030), PDE4AIA (Cat# 60040), PDE5A1 (Cat# 60050), PDE6C (Cat#
60060), PDE7A (Cat# 60070), PDE8A1 (Cat# 60080), PDE9A2 (Cat#
60090), PDE11A4 (Cat# 60110).
[0136] Assays for PDE 1 through 11 were performed in parallel at
room temperature in 384-well microtiter plates with an incubation
volume of 20.2 .mu.L. Solutions of test compounds were prepared in
DMSO and serially diluted with DMSO to yield 30 .mu.L of each of
ten solutions differing by 3-fold in concentration, at 32 serial
dilutions per plate. 100% inhibition was determined by adding
buffer in place of the enzyme and 0% inhibition is determined by
using DMSO (1% final concentrations). A Labcyte POD 810 (Labcyte,
Sunnyvale, Calif.) was used to dispense 200 nL from each well of
the titration plate to make eleven copies of the assay plate for
each titration, one copy for each PDE enzyme. A solution of each
enzyme (dilution from aliquots, sufficient to produce 20% substrate
conversion) and a separate solution of FAM-labeled cAMP or
FAM-labeled cGMP from Molecular Devices (Sunnyvale, Calif., product
# R7506 or cGMP#R7508), at a final concentration of 50 nM were made
in the assay buffer (10 mM Tris HCl, pH 7.2, 10 mM MgCl.sub.2,
0.05% NaN.sub.3 0.01% Tween-20, and 1 mM DTT). Note that the
substrate for PDE2 is 50 nM FAM cAMP containing 1000 nM of cGMP.
The enzyme and the substrate were then added to the assay plates in
two consecutive additions of 10 .mu.L and then shaken to mix. The
reaction was allowed to proceed at room temperature for 60 minutes.
A binding solution was then made from the kit components, comprised
of 80% Solution A, 20% Solution B and binding reagent at a volume
of 1/600 the total binding solution. The enzymatic reaction was
stopped by addition of 60 .mu.L of the binding solution to each
well of the assay plate. The plates were sealed and shaken for 10
seconds. The plates were incubated at room temperature for one
hour, then the parallel and perpendicular fluorescence was measured
using a Tecan Genios Pro plate reader (Tecan, Switzerland). The
apparent inhibition constants for the compounds against all 11
PDE's was determined from the parallel and perpendicular
fluorescent readings as described for PDE10 FP assay using the
following apparent K.sub.M values for each enzyme and substrate
combination: PDE1A (FAM cGMP) 70 nM, rhesus PD2A3 (FAM cAMP) 10,000
nM, PDE3A (FAM cAMP) 50 nM, PDE4A1A (FAM cAMP) 1500 nM, PDE5A1 (FAM
cGMP) 400 nM, PDE6C (FAM cGMP) 700 nM, PDE7A (FAM cAMP) 150 nM,
PDE8A1 (FAM cAMP) 50 nM, PDE9A2 (PAM cGMP) 60 nM, PDE10A2 (FAM
cAMP) 150 nM, PDE11A4 (FAM cAMP) 1000 nM. The intrinsic PDE10
inhibitory activity of a compound which may be used in accordance
with the present invention may be determined by these assays.
[0137] The compounds of the following examples had activity in
inhibiting the human PDE10 enzyme in the aforementioned assays,
generally with an Ki of less than about 1 .mu.M. Many of compounds
within the present invention had activity in inhibiting the human
PDE10 enzyme in the aforementioned assays, generally with an Ki of
less than about 0.1 .mu.M. Additional data is provided in the
following Examples. Such a result is indicative of the intrinsic
activity of the compounds in use as inhibitors of the PDE10 enzyme.
In general, one of ordinary skill in the art would appreciate that
a substance is considered to effectively inhibit PDE10 activity if
it has a Ki of less than or about 1 .mu.M, preferably less than or
about 0.1 .mu.M. The present invention also includes compounds
within the generic scope of the invention which possess activity as
inhibitors of other phosphodiesterase enzymes.
[0138] The subject compounds are further useful in a method for the
prevention, treatment, control, amelioration, or reduction of risk
of the diseases, disorders and conditions noted herein. The subject
compounds are further useful in a method for the prevention,
treatment, control, amelioration, or reduction of risk of the
aforementioned diseases, disorders and conditions in combination
with other agents. The compounds of the present invention may be
used in combination with one or more other drugs in the treatment,
prevention, control, amelioration, or reduction of risk of diseases
or conditions for which compounds of the present invention or the
other drugs may have utility, where the combination of the drugs
together are safer or more effective than either drug alone. Such
other drug(s) may be administered, by a route and in an amount
commonly used therefor, contemporaneously or sequentially with a
compound of the present invention. When a compound of the present
invention is used contemporaneously with one or more other drugs, a
pharmaceutical composition in unit dosage form containing such
other drugs and the compound of the present invention may be
desirable. However, the combination therapy may also includes
therapies in which the compound of the present invention and one or
more other drugs are administered on different overlapping
schedules. It is also contemplated that when used in combination
with one or more other active ingredients, the compounds of the
present invention and the other active ingredients may be used in
lower doses than when each is used singly. Accordingly, the
pharmaceutical compositions of the present invention include those
that contain one or more other active ingredients, in addition to a
compound of the present invention. The above combinations include
combinations of a compound of the present invention not only with
one other active compound, but also with two or more other active
compounds. Likewise, compounds of the present invention may be used
in combination with other drugs that are used in the prevention,
treatment, control, amelioration, or reduction of risk of the
diseases or conditions for which compounds of the present invention
are useful. Such other drugs may be administered, by a route and in
an amount commonly used therefor, contemporaneously or sequentially
with a compound of the present invention. Accordingly, the
pharmaceutical compositions of the present invention include those
that also contain one or more other active ingredients, in addition
to a compound of the present invention. The weight ratio of the
compound of the present invention to the second active ingredient
may be varied and will depend upon the effective dose of each
ingredient. Generally, an effective dose of each will be used.
Thus, for example, when a compound of the present invention is
combined with another agent, the weight ratio of the compound of
the present invention to the other agent will generally range from
about 1000:1 to about 1:1000, such as about 200:1 to about 1:200.
Combinations of a compound of the present invention and other
active ingredients will generally also be within the aforementioned
range, but in each case, an effective dose of each active
ingredient should be used.
[0139] In such combinations the compound of the present invention
and other active agents may be administered separately or in
conjunction. In addition, the administration of one element may be
prior to, concurrent to, or subsequent to the administration of
other agent(s).
[0140] Accordingly, the subject compounds may be used alone or in
combination with other agents which are known to be beneficial in
the subject indications or other drugs that affect receptors or
enzymes that either increase the efficacy, safety, convenience, or
reduce unwanted side effects or toxicity of the compounds of the
present invention. The subject compound and the other agent may be
co-administered, either in concomitant therapy or in a fixed
combination.
[0141] In one embodiment, the subject compound may be employed in
combination with anti-Alzheimer's agents, beta-secretase
inhibitors, gamma-secretase inhibitors, HMG-CoA reductase
inhibitors, NSAID's including ibuprofen, vitamin E, and
anti-amyloid antibodies.
[0142] In another embodiment, the subject compound may be employed
in combination with sedatives, hypnotics, anxiolytics,
antipsychotics, antianxiety agents, cyclopyrrolones,
imidazopyridines, pyrazolopyrimidines, minor tranquilizers,
melatonin agonists and antagonists, melatonergic agents,
benzodiazepines, barbiturates, 5HT-2 antagonists, and the like,
such as: adinazolam, allobarbital, alonimid, alprazolam,
amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole,
atypical antipsychotics, bentazepam, benzoctamine, brotizolam,
bupropion, busprione, butabarbital, butalbital, capuride,
carbocloral, chloral betaine, chloral hydrate, clomipramine,
clonazepam, cloperidone, clorazepate, chlordiazepoxide, clorethate,
chlorpromazine, clozapine, cyprazepam, desipramine, dexclamol,
diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin,
estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam,
flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine,
fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine,
imipramine, lithium, lorazepam, lormetazepam, maprotiline,
mecloqualone, melatonin, mephobarbital, meprobamate, methaqualone,
midaflur, midazolam, nefazodone, nisobamate, nitrazepam,
nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine,
pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital,
prazepam, promethazine, propofol, protriptyline, quazepam,
quetiapine, reclazepam, risperidone, roletamide, secobarbital,
sertraline, suproclone, temazepam, thioridazine, thiothixene,
tracazolate, tranylcypromaine, trazodone, triazolam, trepipam,
tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine,
uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem,
and salts thereof, and combinations thereof, and the like, or the
subject compound may be administered in conjunction with the use of
physical methods such as with light therapy or electrical
stimulation.
[0143] In another embodiment, the subject compound may be employed
in combination with levodopa (with or without a selective
extracerebral decarboxylase inhibitor such as carbidopa or
benserazide), anticholinergics such as biperiden (optionally as its
hydrochloride or lactate salt) and trihexyphenidyl (benzhexol)
hydrochloride, COMT inhibitors such as entacapone, MOA-B
inhibitors, antioxidants, A2a adenosine receptor antagonists,
cholinergic agonists, NMDA receptor antagonists, serotonin receptor
antagonists and dopamine receptor agonists such as alentemol,
bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and
pramipexole. It will be appreciated that the dopamine agonist may
be in the form of a pharmaceutically acceptable salt, for example,
alentemol hydrobromide, bromocriptine mesylate, fenoldopam
mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride
and pramipexol are commonly used in a non-salt form.
[0144] In another embodiment, the subject compound may be employed
in combination with a compound from the phenothiazine,
thioxanthene, heterocyclic dibenzazepine, butyrophenone,
diphenylbutylpiperidine and indolone classes of neuroleptic agent.
Suitable examples of phenothiazines include chlorpromazine,
mesoridazine, thioridazine, acetophenazine, fluphenazine,
perphenazine and trifluoperazine. Suitable examples of
thioxanthenes include chlorprothixene and thiothixene. An example
of a dibenzazepine is clozapine. An example of a butyrophenone is
haloperidol. An example of a diphenylbutylpiperidine is pimozide.
An example of an indolone is molindolone. Other neuroleptic agents
include loxapine, sulpiride and risperidone. It will be appreciated
that the neuroleptic agents when used in combination with the
subject compound may be in the form of a pharmaceutically
acceptable salt, for example, chlorpromazine hydrochloride,
mesoridazine besylate, thioridazine hydrochloride, acetophenazine
maleate, fluphenazine hydrochloride, flutphenazine enathate,
fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene
hydrochloride, haloperidol decanoate, loxapine succinate and
molindone hydrochloride. Perphenazine, chlorprothixene, clozapine,
haloperidol, pimozide and risperidone are commonly used in a
non-salt form. Thus, the subject compound may be employed in
combination with acetophenazine, alentemol, aripiprazole,
amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine,
chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine,
haloperidol, levodopa, levodopa with benserazide, levodopa with
carbidopa, lisuride, loxapine, mesoridazine, molindolone,
naxagolide, olanzapine, pergolide, perphenazine, pimozide,
pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine,
trihexyphenidyl, thioridazine, thiothixene, trifluoperazine or
ziprasidone.
[0145] In another embodiment, the subject compound may be employed
in combination with an anti-depressant or anti-anxiety agent,
including norepinephrine reuptake inhibitors (including tertiary
amine tricyclics and secondary amine tricyclics), selective
serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors
(MAOIs), reversible inhibitors of monoamine oxidase (RIMAs),
serotonin and noradrenaline reuptake inhibitors (SNRIs),
corticotropin releasing factor (CRF) antagonists, a-adrenoreceptor
antagonists, neurokinin-1 receptor antagonists, atypical
anti-depressants, benzodiazepines, 5-HT.sub.1A agonists or
antagonists, especially 5-HT.sub.1A partial agonists, and
corticotropin releasing factor (CRF) antagonists. Specific agents
include: amitriptyline, clomipramine, doxepin, imipramine and
trimipramine; amoxapine, desipramine, maprotiline, nortriptyline
and protriptyline; fluoxetine, fluvoxamine, paroxetine and
sertraline; isocarboxazid, phenelzine, tranylcypromine and
selegiline; moclobemide: venlafaxine; duloxetine; aprepitant;
bupropion, lithium, nefazodone, trazodone and viloxazine;
alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam,
halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan,
gepirone and ipsapirone, and pharmaceutically acceptable salts
thereof.
[0146] The compounds of the present invention may be administered
by oral, parenteral (e.g., intramuscular, intraperitoneal,
intravenous, ICV, intracisternal injection or infusion,
subcutaneous injection, or implant), by inhalation spray, nasal,
vaginal, rectal, sublingual, or topical routes of administration
and may be formulated, alone or together, in suitable dosage unit
formulations containing conventional non-toxic pharmaceutically
acceptable carriers, adjuvants and vehicles appropriate for each
route of administration. In addition to the treatment of
warm-blooded animals such as mice, rats, horses, cattle, sheep,
dogs, cats, monkeys, etc., the compounds of the invention are
effective for use in humans. The terms "administration of" and or
"administering a" compound should be understood to mean providing a
compound of the invention or a prodrug of a compound of the
invention to the individual in need of treatment.
[0147] The term "composition" as used herein is intended to
encompass a product comprising specified ingredients in
predetermined amounts or proportions, as well as any product which
results, directly or indirectly, from combination of the specified
ingredients in the specified amounts. Such term in relation to
pharmaceutical composition, is intended to encompass a product
comprising the active ingredient(s), and the inert ingredient(s)
that make up the carrier, as well as any product which results,
directly or indirectly, from combination, complexation or
aggregation of any two or more of the ingredients, or from
dissociation of one or more of the ingredients, or from other types
of reactions or interactions of one or more of the ingredients. In
general, pharmaceutical compositions are prepared by uniformly and
intimately bringing the active ingredient into association with a
liquid carrier or a finely divided solid carrier or both, and then,
if necessary, shaping the product into the desired formulation. In
the pharmaceutical composition the active object compound is
included in an amount sufficient to produce the desired effect upon
the process or condition of diseases. Accordingly, the
pharmaceutical compositions of the present invention encompass any
composition made by mixing a compound of the present invention and
a pharmaceutically acceptable carrier.
[0148] Pharmaceutical compositions intended for oral use may be
prepared according to any method known to the art for the
manufacture of pharmaceutical compositions and such compositions
may contain one or more agents selected from the group consisting
of sweetening agents, flavoring agents, coloring agents and
preserving agents in order to provide pharmaceutically elegant and
palatable preparations. Tablets contain the active ingredient in
admixture with non-toxic pharmaceutically acceptable excipients
that are suitable for the manufacture of tablets. The tablets may
be uncoated or they may be coated by known techniques to delay
disintegration and absorption in the gastrointestinal tract and
thereby provide a sustained action over a longer period.
Compositions for oral use may also be presented as hard gelatin
capsules wherein the active ingredients are mixed with an inert
solid diluent, for example, calcium carbonate, calcium phosphate or
kaolin, or as soft gelatin capsules wherein the active ingredient
is mixed with water or an oil medium, for example peanut oil,
liquid paraffin, or olive oil. Aqueous suspensions, oily
suspensions, dispersible powders or granules, oil-in-water
emulsions, and sterile injectable aqueous or oleagenous suspension
may be prepared by standard methods known in the art. By
"pharmaceutically acceptable" it is meant the carrier, diluent or
excipient must be compatible with the other ingredients of the
formulation and not deleterious to the recipient thereof.
[0149] The subject compounds are further useful in a method for the
prevention, treatment, control, amelioration, or reduction of risk
of the diseases, disorders and conditions noted herein. The dosage
of active ingredient in the compositions of this invention may be
varied, however, it is necessary that the amount of the active
ingredient be such that a suitable dosage form is obtained. The
active ingredient may be administered to patients (animals and
human) in need of such treatment in dosages that will provide
optimal pharmaceutical efficacy. The selected dosage depends upon
the desired therapeutic effect, on the route of administration, and
on the duration of the treatment. The dose will vary from patient
to patient depending upon the nature and severity of disease, the
patient's weight, special diets then being followed by a patient,
concurrent medication, and other factors which those skilled in the
art will recognize. Generally, dosage levels of between 0.001 to 10
mg/kg. of body weight daily are administered to the patient, e.g.,
humans and elderly humans. The dosage range will generally be about
0.5 mg to 1.0 g. per patient per day which may be administered in
single or multiple doses. In one embodiment, the dosage range will
be about 0.5 mg to 500 mg per patient per day; in another
embodiment about 0.5 mg to 200 mg per patient per day; and in yet
another embodiment about 5 mg to 50 mg per patient per day.
Pharmaceutical compositions of the present invention may be
provided in a solid dosage formulation such as comprising about 0.5
mg to 500 mg active ingredient, or comprising about 1 mg to 250 mg
active ingredient. The pharmaceutical composition may be provided
in a solid dosage formulation comprising about 1 mg, 5 mg, 10 mg,
25 mg, 50 mg, 100 mg, 200 mg or 250 mg active ingredient. For oral
administration, the compositions may be provided in the form of
tablets containing 1.0 to 1000 milligrams of the active ingredient,
such as 1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400,
500, 600, 750, 800, 900, and 1000 milligrams of the active
ingredient for the symptomatic adjustment of the dosage to the
patient to be treated. The compounds may be administered on a
regimen of 1 to 4 times per day, such as once or twice per day.
[0150] Several methods for preparing the compounds of this
invention are illustrated in the following Schemes and Examples.
Starting materials and the requisite intermediates are in some
cases commercially available, or can be prepared according to
literature procedures or as illustrated herein. The compounds of
this invention may be prepared by employing reactions as shown in
the following schemes, in addition to other standard manipulations
that are known in the literature or exemplified in the experimental
procedures. Substituent numbering as shown in the schemes does not
necessarily correlate to that used in the claims and often, for
clarity, a single substituent is shown attached to the compound
where multiple substituents are allowed under the definitions
hereinabove. Reactions used to generate the compounds of this
invention are prepared by employing reactions as shown in the
schemes and examples herein, in addition to other standard
manipulations such as ester hydrolysis, cleavage of protecting
groups, etc., as may be known in the literature or exemplified in
the experimental procedures. Starting materials are made according
to procedures known in the art or as illustrated herein. The
following abbreviations are used herein: Me: methyl; Et: ethyl;
t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; Bn: benzyl; Ac: acetyl;
Cbz: benzyl carbamate; THF: tetrahydrofuran; Boc:
tert-butyloxycarbonyl; DIPEA: N,N-diisopropylethylamine; DPPA:
diphenylphosphorylazide; DMAP: 4-dimethylaminopyridine; DMSO:
dimethylsulfoxide; EDC:
N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide; EtOAc: ethyl
acetate; HOAt: 1-hydroxy-7-azabenzotriazole; HOBt:
hydroxybenzotriazole hydrate; TEA: triethylamine; DMF:
N,N-dimethylformamide; rt: room temperature; HPLC: high performance
liquid chromatography; NMR: nuclear magnetic resonance; TLC:
thin-layer chromatography.
[0151] In some cases the final product may be further modified, for
example, by manipulation of substituents. These manipulations may
include, but are not limited to, reduction, oxidation, alkylation,
acylation, and hydrolysis reactions which are commonly known to
those skilled in the art. In some cases the order of carrying out
the foregoing reaction schemes may be varied to facilitate the
reaction or to avoid unwanted reaction products. The following
examples are provided so that the-invention might be-more
fully-understood. These examples are illustrative only and should
not be construed as limiting the invention in any way.
##STR00014##
[0152] Hydroxymethyl pyridine derivatives can be readily converted
to their corresponding chloromethyl pyridyl HCl salts (A-1) by
treatment with thionyl chloride. Alkylation of commercially
available phenolic boronate esters with A-1 under standard
conditions provides elaborated boronate esters A-2.
##STR00015##
[0153] Highly selective C--N cross couplings of variably
functionlized 2-chloro-3-iodopyridines with a variety of primary
and secondary amines furnishes 2-chloro-3-aminopyridines B-1.
High-yielding Suzuki cross couplings with A-2 under standard
conditions furnishes the fully elaborated products of the formula
B-2 of the present invention.
##STR00016##
[0154] The synthetic scheme outlined in Generic Scheme B can be
readily applied to any chloro-iodopyridine isomer to furnish all
possible regioisomeric pyridine backbones of the current invention.
As illustrated in Generic Scheme C, 3-iodo-4-chloropyridine can be
used under otherwise identical conditions to furnish fully
elaborated products of the formula C-2. 3-chloro-4-iodopyridine and
2-iodo-3-chloropyridine can be used analogously.
##STR00017##
[0155] A pyrazine group can be incorporated through a tandem
SNAr/Suzuki protocol. Beginning with commercially available
dichloropyrazine, a variety of primary and secondary amines can be
added to furnish the corresponding 2-chloro-3-amino-pyrazines.
These intermediate products can be isolated, or used directly in a
one-pot procedure. As such, boronate esters of the form A-2 can be
coupled to afford products of the formula D-1 of the present
invention.
EXAMPLE 1
##STR00018##
[0156] 2-(chloromethyl)-3,4-dimethoxypyridine hydrochloride
(1-1)
[0157] A solution of (3,4-dimethoxypyridin-2-yl)methanol (1 g, 5.91
mmol) in CH.sub.2CH.sub.2 (11.82 mL) was treated dropwise with
thionyl chloride (1 mL, 13.70 mmol) with stirring at room
temperature. The reaction mixture was stirred for 2 h, and then
concentrated directly in vacuo. The resulting residue was washed
with 3.times.10 mL Et.sub.2O, the resulting solids collected by
filtration, and then dried under reduced pressure to afford the
title compound as a white solid (1.12 g, 85%), which was used in
the subsequent step without further purification. Data for 1-1:
LC/MS: rt=0.58 min, m/z (M+H)=188.09 found; 188.04 required.
3,4-dimethoxy-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-
methyl}-pyridine (1-2)
[0158] 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (100
mg, 0.454 mmol), 1-1 (85 mg, 0.454 mmol), and K.sub.2CO.sub.3 (157
mg, 1.136 mmol) were combined in a 50-mL round bottom flask with a
stirbar. DMF (3.03 mL) was added, and the reaction mixture was
heated to 90.degree. C. for 4 h. The reaction mixture was diluted
with EtOAc (30 mL), and washed sequentially with sat. aq.
NaHCO.sub.3 (30 mL) and brine (30 mL). The combined organics were
dried over MgSO.sub.4, filtered, and concentrated in vacuo to
afford the title compound as a tan solid (155 mg, 78%, >85%
pure), which was used in the subsequent step without further
purification. Data for 1-2: LC/MS: rt=1.78 min, m/z (M+H)=372.19
found; 372.19 required.
EXAMPLE 2
##STR00019##
[0159] 4-(2-chloropyridin-3-yl)morpholine (2-1)
[0160] A 2-dram vial equipped with a stirbar was charged with
Pd(OAc).sub.2 (0.234 g, 1.044 mmol) and rac-BINAP (0.683 g, 1.096
mmol) as solids. Toluene (4 mL) was added via syringe, and the
mixture was stirred for 10 min while being degassed with argon, and
until a uniform tan suspension resulted. A 100-mL round-bottom
flask was charged with 2-chloro-3-iodopyridine (1.25 g, 5.22 mmol)
and Cs.sub.2CO.sub.3 (7.14 g, 21.93 mmol). Toluene (34.8 mL) was
added followed by morpholine (0.542 ml, 6.26 mmol). This solution
was degassed for 1 min under argon, and then the catalyst/ligand
suspension was added via pasteur pipette. A reflux condenser was
attached to the flask, and the reaction mixture was refluxed at
120.degree. C. for 16 h. The reaction mixture was concentrated in
vacuo, and then diluted with CH.sub.2Cl.sub.2 (150 mL). The
organics were washed with 2.times.100 mL brine, dried over
Na.sub.2SO.sub.4, filtered, and concentrated in vacuo. The material
was purified by gradient elution on silica gel (5 to 75% [5%
MeOH/EtOAc] in hexanes) to afford the title compound as light
yellow solid (700 mg, 64%). Data for 2-1: .sup.1H NMR (500 MHz,
CDCl.sub.3) d 8.08 (dd, J=4.4, 1.5 Hz, 1H), 7.32 (dd, J=7.8, 1.5
Hz, 1H), 7.21 (dd, J=7.8, 4.5 Hz, 1H), 3.89 (dd, J=4.5, 4.5 Hz,
4H), 3.08 (dd, J=4.5, 4.5 Hz, 4H); HRMS m/z (M+H) 199.0630 found,
199.0633 required.
[0161]
4-(2-{4-[(3,4-dimethoxypyridin-2-yl)methoxy]phenyl}pyridin-3-yl)mor-
pholine (2-2)
[0162] A solution of 2-2 (28.0 mg, 0.076 mmol) in DMF (378 .mu.l)
was degassed under argon for 5 min. Next, 2-1 (15 mg, 0.076 mmol),
Pd(PPh.sub.3).sub.4 (17.45 mg, 0.015 mmol), and Cs.sub.2CO.sub.3
(61.5 mg, 0.189 mmol) were added in one portion as solids, and the
reaction mixture was stirred at 90.degree. C. for 2 h. The reaction
mixture was diluted with EtOAc (10 mL) and washed sequentially with
sat. aq. NaHCO.sub.3 (10 mL) and brine (10 mL). The combined
organics were-dried over MgSO4, filtered, and concentrated in
vacuo. The material was purified by gradient elution on silica gel
(10 to 100% [5% MeOH/EtOAc] in hexanes) to afford the title
compound as an off-white solid (21.3 mg, 65.8%). Data for 2-2:
.sup.1H NMR (500 MHz, CDCl.sub.3) d 8.32 (dd, J=4.6, 1.2 Hz, 1H),
8.30 (d, J=5.5 Hz, 1H), 7.93 (d, J=8.8 Hz, 2H), 7.29 (dd, J=8.1,
1.2 Hz, 1H), 7.15 (dd, J=8.1, 4.6 Hz, 1H), 7.10 (d, J=8.8 Hz, 2H),
6.86 (d, J=5.5 Hz, 1H), 5.24 (s, 2H), 3.94 (s, 3H), 3.91 (s, 3H),
3.68 (dd, J=4.6, 4.6, 4H), 2.85 (dd, J=4.6, 4.6 Hz, 4H); HRMS m/z
(M+H) 408.1918 found, 408.1918 required.
EXAMPLE 3
##STR00020##
[0163] 2-chloro-3-[3-(3 -methylphenyl)piperidin-1-yl]pyridine
(3-1)
[0164] Dichloropyrazine (100 mg, 0.454 mmol),
3-(3-methylphenyl)piperidine hydrochloride (85 mg, 0.454 mmol), and
K.sub.2CO.sub.3 (157 mg, 1.136 mmol) were combined in a 25-mL round
bottom flask with a stirbar. DMF (4.48 mL) was added, and the
reaction mixture was heated to 50.degree. C. for 4 h. The reaction
mixture was diluted with EtOAc (20 mL), and washed sequentially
with sat. aq. NaHCO.sub.3 (20 mL) and brine (20 mL). The combined
organics were dried over MgSO.sub.4, filtered, and concentrated in
vacuo to afford the title compound as a brown gum (155 mg, 76%),
which was used in the subsequent step without further purification.
Data for H-1: LC/MS: rt=3.17 min, m/z (M+H)=288.15 found; 288.79
required.
[0165]
3,5-dimethoxy-4-methyl-2-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborola-
n-2-yl)phenoxy]methyl}pyridine (3-2)
[0166] The title compound was prepared according to the protocol
described in Example 1, substituting the requisite starting
materials. Data for 3-2: LC/MS: rt=1.77 min, m/z (M+H)=370.18
found; 370.26 required.
[0167] 2-{4-[(3,5-dimethoxy-4-methylpyridin-2-yl)methoxy]phenyl}-3-
[3-(3-methylphenyl)-piperidin-1-yl]pyrazine (3-3)
[0168] A solution of H-1 (25.0 mg, 0.087 mmol) in DMF (579 .mu.l)
was degassed under argon for 5 min. Next, H-2 (32.1 mg, 0.087
mmol), Pd(PPh.sub.3).sub.4 (20.1 mg, 0.017 mmol), and
Cs.sub.2CO.sub.3 (70.8 mg, 0.217 mmol) were added in one portion as
solids, and the reaction mixture was stirred at 90.degree. C. for 2
h. The reaction mixture was diluted with EtOAc (10 mL) and washed
sequentially with sat. aq. NaHCO.sub.3 (10 mL) and brine (10 mL).
The combined organics were dried over MgSO.sub.4, filtered, and
concentrated in vacuo. The material was purified by gradient
elution on silica gel (10 to 50% [5% MeOH/EtOAc] in hexanes) to
afford the title compound as a white solid (19.5 mg, 40.8%). Data
for H-3: .sup.1H NMR (500 MHz, CDCl.sub.3) d 8.25 (br s, 1H), 8.09
(d, J=2.6 Hz, 1H), 8.02 (d, J=2.6 Hz, 1H), 7.90 (d, J=8.8 Hz, 2H),
7.13 (d, J=8.8 Hz, 2H), 7.10-7.15 (m, 1H), 6.98-7.00 (m, 1H),
6.86-6.89 (m, 2H), 5.24 (s, 2H), 3.78 (s, 3H), 3.72 (dd, J=20.3,
14.4 Hz, 1H), 2.74-2.80 (m, 1H), 2.60-2.71 (m, 2H), 2.35 (s, 3H),
2.29 (s, 3H), 2.27 (s, 3H), 1.99 (br d, J=12.2 Hz, 1H), 1.58-1.78
(m, 4H); HRMS m/z (M+H) 495.2753 found, 495.2755 required.
TABLE-US-00001 TABLE 1 The following compounds were prepared using
the foregoing methodology, but substituting the appropriately
substituted reagent, as described in the foregoing Reaction Schemes
and Examples. Cpd. Structure Name HRMS m/z (M + H) 4 ##STR00021##
6-(3-{4-[(4-methoxy- 3,5-dimethylpyridin- 2-yl)-methoxy]-
phenyl}pyridin-2-yl)- 5,6,7,8-tetrahydro- 1,6-naphthyridine
453.2288 found, 453.2285 required. 5 ##STR00022## 2-{4-[(4-methoxy-
3,5-dimethylpyridin-2- yl)methoxy]phenyl}- N-methyl-N-(pyridin-
4-ylmethyl)pyridin-3- amine 441.2287 found, 441.2285 required. 6
##STR00023## 7-({4-[3-(2-pyridin- 3-ylmorpholin-4- yl)pyridin-2-
yl]phenoxy}methyl)- 1,2,3,4-tetrahydro- 1,8-naphthyridine 480.2389
found, 480.2394 required. 7 ##STR00024## N-(pyridin-4-
ylmethyl)-2-[4- (5,6,7,8-tetrahydro- 1,8-naphthyridin-2-
ylmethoxy)phenyl] pyridin-3-amine 424.2128 found, 424.2132
required. 8 ##STR00025## 2-({4-[3-(3,4- dihydroisoquinolin-
2(1H)-yl)pyridin-2- yl]phenoxy}methyl) quinoline 444.2067 found,
444.2070 required. 9 ##STR00026## 7-{2-[4-(quinolin-2-
ylmethoxy)phenyl] pyridin-3-yl}-6,7,8,9- tetrahydropyrido[2,3 -
b]-1,6-naphthyridine HRMS m/z (M + H) 496.2116 found, 496.2132
required. 10 ##STR00027## 6-(2-{4-[(4-methoxy- 3,5-dimethylpyridin-
2-yl)methoxy] phenyl}pyridin-3- yl)-5,6,7,8- tetrahydro-1,6-
naphthyridine 453.2288 found, 453.2285 required. 11 ##STR00028##
N-ethyl-N-pyridin-3- yl-2-[4-(quinolin-2- ylmethoxy)phenyl]
pyridin-3-amine 433.2022 found, 433.2023 required. 12 ##STR00029##
2-({4-[3-(2-pyridin- 3-ylmorpholin-4- yl)pyridin-2-
yl]phenoxy}methyl) quinoline 475.2122 found, 475.2129 required. 13
##STR00030## 4-(2-{3-chloro-5- methoxy-4-[(4- methoxy-3,5-
dimethylpyridin-2- yl)methoxy]phenyl} pyridin-3- yl)morpholine
470.1843 found, 470.1841 required. 14 ##STR00031## 2-({4-[3-(2,3-
dihydro-1H- pyrrolo[2,3- c]pyridin-1- yl)pyridin-2- yl]phenoxy}-
methyl)quinoline 431.1855 found, 431.1866 required. 1-5
##STR00032## 6-(2-{4-[(6- methylpyridin-2- yl)methoxy]phenyl}
pyridin-3-yl)-3- (trifluoromethyl)- 5,6,7,8-tetrahydro-
1,6-naphthyridine 477.1901 found, 477.1897 required. 16
##STR00033## 6-(5-fluoro-2-{4-[(4- methoxy-3,5- dimethylpyridin-2-
yl)methoxy]phenyl} pyridin-3-yl)-5,6,7,8- tetrahydro-1,6-
naphthyridine 471.2178 found, 471.2191 required. 17 ##STR00034##
4-[2-(4-{[5- (trifluoromethyl) pyridin-2- yl]methoxy}phenyl)
pyridin-3- yl]morpholine 416.1581 found, 416.1580 required. 18
##STR00035## 6-{4-[4-(quinolin-2- ylmethoxy)phenyl]
pyridin-3-yl}-5,6,7,8- tetrahydro-1,6- naphthyridine HRMS m/z (M +
H) 445.2022 found, 445.2023 required. 19 ##STR00036##
6-{3-[4-(5,6,7,8- tetrahydro-1,8- naphthyridin-2- ylmethoxy)phenyl]
pyrazin-2-yl}-5,6,7,8- tetrahydro-1,6- naphthyridine 451.2238
found, 451.2241 required. The requisite starting materials were
commercially available, described in the literature, or readily
synthesized by one skilled in the art of organic synthesis without
undue experimentation. Final products were purified by either
gradient elution on SiO.sub.2 (EtOAc/hexanes or
MeOH/CH.sub.2Cl.sub.2), reverse phase flash chromatography
(MeCN/H.sub.2O), or preparative thin layer chromatography
(EtOAc/hexanes or MeOH/CH.sub.2Cl.sub.2 or MeOH/EtOAc), and were
isolated as free-bases.
[0169] While the invention has been described and illustrated with
reference to certain particular embodiments thereof, those skilled
in the art will appreciate that various adaptations, changes,
modifications, substitutions, deletions, or additions of procedures
and protocols may be made without departing from the spirit and
scope of the invention.
* * * * *